Process of making rho-aminobenzenesulphonamidopyrimidines



Patented Oct. 14, 1947 PROCESS OF MAKING II-AMINOBENZENE-BULPHONAMIDOPYRIMIDINES Max Hartmann, Biehen, Harald von Meyenburg,Basel, and Jean Druey, Riehen, Switzerland, auignore to ClbaPharmaceutical Products, Incorporated, Summit, N. 1., a corporation ofNew Jersey No Drawing.

Application March 9, 1943, Serial No. 478,554. In Switzerland March 5,1042 Claims. (01. 260-2393) It is known thatp-aminobenzenesulphonamidopyrimidines can be prepared by causing certainbenzesulphonic acid halides to react with aminopyrimidines and, iinecessary, forming the amino group in the resultant aminopyrimidinessubstituted by one benzenesulphonyl radical.

The surprising observation was made that, in this reaction, undercertain conditions, 2-, or 4- (identical with dl-aminopyrimidinessubstituted by two identical benzenesulphonyl radicals are formed fromthe corresponding 2- or 4(identical with 8) -aminopyrimidines.

It has now been found that p-aminobenzenesulphonamidopyrimidines canalso be obtained when a 2- or flidentical with fll-aminopyrimidine,which is substituted with two identical benzenesulphonyl radicals whosebenzene nuclei contain in the p-position amino-groups or substitutentscapable of conversion into aminogroups. is treated with hydrolyzingagents or is caused to react with the aminopyrimidine from which theaminopyrimidine substituted with two sulphonyl radicals used for thereaction is derived, and it necessary. converting into amino groups thesaid substituents capable of conversion into amino groups in the productobtained.

On treatment with hydrolyzing agents one of the benzenesulphonylradicals is, surprisingly, split on and one molecule of the finalproduct is obtained from one molecule 0! the initial product. If thereaction is carried outwith the aminopyrimidine mentioned, one of thebenzenesulphonyl radicals is similarly split off. Two molecules ofbenzene-sulphonamidopyrimidine are, however, formed from one molecule ofdisubstituted amidopyrimidlne.

As starting product can be used any 2- or 4(ldentical withfll-aminopyrimidine which is substituted with two identicalbenzenesulphonyl radicals and whose benzene nuclei contain in thep-position amino groups or substituents convertible into such. e. g.acylamino-, nitroor azo-groups or halogen atoms. In particular thefollowing substances may be mentioned: Bis- N-(p-acylaminobenzenesulphonyl) 2 aminopyrimidines, such as bis-N-(p-acetylaminobenzenesulphonyl) or bis-N-(p-nitrobenzenesulphonyl)2-aminopyrimidine, -2-amino alkylpyrimidines, such as-2-amino-4-methyl-pyrimidine, -2-amino-4,6-dimethyl-pyrimidine, and-6-amino-alkylpyrimidines, such as -6-amino-2,4-dlmethylpyrimidine.

The treatment with hydrolyzing agents can be carried out in the usualway. e. g, by heating with a base or acid in water. It is also possible,however, to heat in an organic solvent or diluent, e. g. alcohol, in thepresence of a hydrohalide.

The reaction with the aminopyrimidine mentioned is most suitably carriedout in an organic solvent, preferably in pyridine, by heating to a hightemperature.

Known methods may be used for converting into amino groups thesubstituents capable oi conversion into amino groups. Acylaminocompounds, tor example, are saponified, nitro- 0:- a20- compoundsreduced, and halogen compounds caused to react with ammonia.

In order to prepare the aminopyrimidines substituted with twobenzosulphonyl radicals which are used as starting products, a 2- oriiidentical with 6l-aminopyrimidine can be caused to react in an organicsolvent in the presence oi strong bases at ordinary or increasedtemperature (particularly at 4060 C.) with a reactive benzenesulphonicacid derivative, in particular a halide, e. g., a chloride whichpossesses in the p-position an amino group or a substituent capable ofconversion into an amino group, e. g. an acylamino-, nitroor azo-groupor a halogen atom. The reaction can be advantageously carried out inpyridine.

The products 01' the reaction find use a medicaments or as intermediateproducts in the manuiacture of such.

The following examples illustrate the invention, the parts being byweight:

Example 1 49.3 parts of bis-N-(p-nitrobenzenesulphonyll-8-amino-2,4-dimethyl-pyrimidine are heated to boiling for one hour with12.3 parts of G-amino- 2,4-dimethylpyrimidine in 50 parts of drypyridine. After cooling, theG-(p-nitro-benzenesuiphonamido)-2,4-dimethyl-pyrimidine formed isprecipitated with water and filtered ofi by suction. It is purified bydissolving in dilute caustic soda and precipitating with acid. onrecrystallization from dilute alcohol it melts (with decomposition) at188-189 C.

On reduction, for example with iron and hydrochloric acid,d-(p-aminobenzene sulphonamido-2,4-dimethyl-pyrimidine, melting point238 (2., is obtained.

The starting product can be prepared as follows:

123 parts of finely powdered 6-amino-2,4-dimethyl-pyrimidine aresuspended in 250 parts of dry pyridine and 222 parts orp-nitro-benzenesulphonyl chloride added at 50-55' C. The whole is thenwarmed for 2 hours to 55 C. Water is added to the crystalline aggregateobtained, the precipitated bis-N-(p nitrobenzenesulphonyl)6-amino-2,4-dimethyl-pyrimidine filtered off by suction and washed withwater. It is purified by recrystallizing from methyl-ethyl ketone. nslowly heating it decomposes; on rapidly heating it melts at about210-215 C. with decomposition.

Example 2 49.3 parts of bis-N-(p-nitrobenzenesulphonyl)6-amino-2,4-dimethylpyrimidine are boiled under reflux with 140 parts byvolume of 2N caustic soda solution until a clear solution is obtained.After cooling, it is neutralized with concentrated hydrochloric acid. Inthis way G-(p-nitrobenzenesulphonamido) 2,4 dimethylpyrlmidine isobtained, which is purified as described in Example 1 and can beconverted by reduction into 6-(p-aminobenzenesulphonamido)-2,4-dimethylpyrimidine.

Example 3 51.7 parts of bis-N-(p-acetylaminobenzenesuiphonyl) -6-amino2,4 dimethylpyrimidine are heated to boiling for 3 hours under refluxwith 12.3 parts of 6-amino-2,4-dirnethylpyrimidine in 50 parts of drypyridine. After cooling, plenty of water is added and the precipitatedG-(p-acetylamlnobcnzcnesulphonamido) -2,4 dimethylpyrimidine filteredoff by suction. It can be recrystallized from 50% acetic acid, and meltswith decomposition at 310 C.

On saponiflcation of the acetyl group. e. g. on boiling with dilutecaustic soda solution, 6- lp-aminobenzenesulphonamido) 2,4 dimethylpyrimidine is obtained. It can be recrystallized from dilute alcohol andmelts at 236 C.

The starting roduct can be prepared as follows:

120 parts of p-acetylaminobenzenesulphonyl chloride are introduced at50-55 C. into a suspension of 123 parts of finely powdered 6-amino2,4-rlimethylpyrlmidine in 200 parts of dry pyridine. After it has allbeen added, the temperature is kept at 55 C. for one hour and thenheated for one hour to 90-95 C. The pyridine is removed by heating invacuo on a water-bath. The residue is triturated with warm water andfiltered off by suction, thoroughly stirred up with dilute caustic sodasolution, again filtered off and washed with water. Afterrecrystallization from methyl-ethyl ketone, thebis-N-(p-acetylaminobcnzcnesulphonyl) -6-amino-2,4dimethylpyrimidinedecomposes above 225 C. to an increasing extent with rising temperature.

Example 4 51.? parts ofbis-N-(p-acetylaminobenzenesulphonyl)-G-amino-2,4-dimethylpyrimidine areboiled under reflux with 250 parts by volume of 2N caustic soda solutionuntil solution is complctc. The solution is boiled for a further 30minutes, thordughiy stirred up with animal charcoal. filtered and6-(p-aminobenzene-sulphonamidol 2,4 dimethylpyrimidine precipitated fromthe filtrate with hydrochloric acid. After recrystallization from dilutealcohol it melts at 236 C.

Example 49.3 parts of bis-N-(p-nitrobenzenesulphonyl)2-amino-4,fi-dimethylpyrimidine are boiled under reflux for severalhours with 100 parts by volume of 5N caustic soda solution untilsolution occurs. While still hot. it is diluted with 4 400 parts of hotwater and then filtered hot. The 2 (p-nitrobenzenesulphonamido) 4,6dimethyl-pyrimidine is precipitated from the filtrate with hydrochloricacid. It can be recrystallized from dilute alcohol, and melts at 208-210 C.

The same substance is obtained when bis-N- (p-nitrobenzene sulphonyl) 2amino 4,6-dimethylpyrimidine is caused to react with 2-amino-4,6-dimethylpyrimidine in pyridine.

On reduction with iron and hydrochloric acid, 2-p-amlnobenzenesulphonamido) -4,B-dimethylpyrimidine, melting point 177C., is obtained.

The starting product is obtained in the following way:

222 parts of p-nitrobenzene-sulphonyl chloride are added to 61.5 partsof 2-amino-4,6-dimethylpyrimidine in 100 parts of dry pyridine at C. andheated for a few hours to C. The mixture is then diluted with plenty ofwater and the precipitate filtered ofl by suction. The residue issuspended with dilute caustic soda, filtered off by suction, washed withwater and then with acetone. A bright, slightly soluble powder isobtained which can be recrystallized from methylethyl ketone and meltsat 230-232 C. with decomposition.

2-lp-aminobenzenesulphonamido) -pyrimldlne can be prepared in ananalogous way from the corresponding parent product. It melts at 255 C.

What we claim is:

1. A process for the manufacture of apara-aminobenzenesuiphonamidopyrimidine, which comprises reacting onemol of a member selected from the group consisting of the 2- and4-8.1'1'111'10- pyrimidines at a temperature of about 40-60 C. with twomols of a benzenesulphonic acid halide, wherein the benzene nucleuscontains in the para-position a member selected from the groupconsisting of amino, acyiamino, nitro and azo, and treating theresultant aminopyrimidine which is substituted by two identicalbenzenesulphonyl radicals containing in para-position the selectedsubstituent, with the arninopyrimidine selected for the reaction withthe benzene sulphonic acid halide.

2. A process for the manufacture of aparaaminobenzenesulphonamidopyrimidine. which comprises reacting one molof 2-aminopyrimidine at a. temperature of about 40-60 C. with two molsof a para-nitrobenzenesulphonyl halide, treating the resultantbis-N-(para-nitrobenzenesulphonyl)-2-aminopyrimidine withZ-aminopyrimidine in the presence of pyridine, and then treating theproduct with a reducing agent.

3. A process for the manufacture of B-(paraaminobenzenesulphonamido)-2,4 dimethylpyrimidine, which comprises reacting one mol of B-amino-2,4-dimethy1pyrimidine at a temperature or about 40-60 C. with twomols of a para-nitrobenzenesulphonyl halide, treating the resultantbis-N- (para-nitrobenzenesulphonyl) 6 amino- ZA-dimethylpyrimidine withG-amino 2,4 dimethyipyrimidine in the presence of pyridine, and thentreating the resultant product with a. reducing agent,

4. A process for the manufacture of G-(paraaminobenzenesulphonamido) 2,4dimethylpyrimidine. which comprises reacting one mol of 6-amino-z,4-dimethylpyrimidine at a temperature of about 40-60 C. with twomols of a paraacetylaminobenzenesulphonyl halide, treating the resultantbis N (para-acetylaminobenzenesulphonyl) -6-amino-2,4-dimethylpyrimidinewith 6- amino-2,4-dimethylpyrimidine in the presence of 5 pyridine. andthen treating the resultant product with a hrdrolyslnz went.

5. A process for the manufacture or 2-(peraaminobenzenesulphonamido) 4,0dlmethyipyflmidine, which comprises reacting one no! or 2-amino-4.6-dimethylpyrlmidine at a temperature of about 40-64? C. withtwo mole oi a paranitrobenzenesulphonyl halide, treating the resultantbis N (para nitrobenzenesuiphonyl) 2- amino-4.B-dimethylpyrimidlne withi-amino-4,6- 1o dimethylpyrimidine in the presence of pyridine, and thentreating the resultant product with a reducing agent.

MAX HAR'I'MANN. HARALD volt MEYENBURG. JEAN DRUEY.

REFERENCES CITED The following references are 01' record in the me orthis patent:

OTHER REFERENCES Journal Amer. Chem. Soc, vol. 63, pages 578- 580: (Feb.1941); ibid., p les 3028-3080, 3124- 4128 (Nov. 1941); 1bid., vol. 84,races 2340- 15 2342 (Oct. 1942); ib1d., vol. 82. D8888 20024005 (Aug.1940); ibid., vol. 83. P es 2188-2190 (A118. 1941).

Bchriner and Fuson, "Identification or Oraanlc Compounds, 2nd ed. (JohnWiley, New York, 194):Me 48.

Certificate 0! Correction Patent No. 2,429,184.

October 14, 1947.

MAX HARTMANN ET AL. It is hereby certified that errors appear in theprinted epielcifioation of the above numbered patent requiringcorrection as follows: Column 2,

e 28, for "use a read use as; line 48, after the s lleble "amido inserta closing tfinirenthesis and that the said Letters Patent shoul be readwith these corrections erein that the same may conform to the record ofthe case in the Patent Oflice.

Signed and sealed this 16th day of December, A. D. 1947.

THOMAS F. MURPHY,

Assistant flommisst'om of Patents.

5 pyridine. and then treating the resultant product with a hrdrolyslnzwent.

5. A process for the manufacture or 2-(peraaminobenzenesulphonamido) 4,0dlmethyipyflmidine, which comprises reacting one no! or 2-amino-4.6-dimethylpyrlmidine at a temperature of about 40-64? C. withtwo mole oi a paranitrobenzenesulphonyl halide, treating the resultantbis N (para nitrobenzenesuiphonyl) 2- amino-4.B-dimethylpyrimidlne withi-amino-4,6- 1o dimethylpyrimidine in the presence of pyridine, and thentreating the resultant product with a reducing agent.

MAX HAR'I'MANN. HARALD volt JEAN DRUEY.

REFERENCES CITED The following references are 01' record in the me orthis patent:

OTHER CES Journal Amer. Chem. Soc, vol. 63, pages 578- 580: (Feb. 1941);ibid., p les 3028-3080, 3124- 4128 (Nov. 1941); 1bid., vol. 84, races2340- 15 2342 (Oct. 1942); ib1d., vol. 82. D8888 20024005 (Aug. 1940);ibid., vol. 83. P es 2188-2190 (A118. 1941).

Bchriner and Fuson, "Identification or Oraanlc Compounds, 2nd ed. (JohnWiley, New York, 194):Me 48.

Certificate 0! Correction Patent No. 2,429,184.

October 14, 1947.

MAX HARTMANN ET AL. It is hereby certified that errors appear in theprinted epielcifioation of the above numbered patent requiringcorrection as follows: Column 2,

e 28, for "use a read use as; line 48, after the s lleble "amido inserta closing tfinirenthesis and that the said Letters Patent shoul be readwith these corrections erein that the same may conform to the record ofthe case in the Patent Oflice.

Signed and sealed this 16th day of December, A. D. 1947.

THOMAS F. MURPHY,

Assistant flommisst'om of Patents.

